WO2015008066A1 - Cyclodextrine - Google Patents

Cyclodextrine Download PDF

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Publication number
WO2015008066A1
WO2015008066A1 PCT/GB2014/052173 GB2014052173W WO2015008066A1 WO 2015008066 A1 WO2015008066 A1 WO 2015008066A1 GB 2014052173 W GB2014052173 W GB 2014052173W WO 2015008066 A1 WO2015008066 A1 WO 2015008066A1
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WO
WIPO (PCT)
Prior art keywords
cyclodextrin
substitution
sbe
reaction
ether
Prior art date
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PCT/GB2014/052173
Other languages
English (en)
Inventor
Tammy Savage
Stephen Wicks
John Mitchell
Original Assignee
Curadev Pharma Pvt Ltd
The University Of Greenwich
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Family has litigation
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Application filed by Curadev Pharma Pvt Ltd, The University Of Greenwich filed Critical Curadev Pharma Pvt Ltd
Priority to KR1020167003973A priority Critical patent/KR20160031019A/ko
Priority to CN201480040709.2A priority patent/CN105431458A/zh
Priority to AU2014291800A priority patent/AU2014291800A1/en
Priority to MX2016000553A priority patent/MX2016000553A/es
Priority to CA2919501A priority patent/CA2919501A1/fr
Priority to EP14742322.2A priority patent/EP3022231B1/fr
Priority to JP2016526700A priority patent/JP2016525600A/ja
Priority to AP2016008975A priority patent/AP2016008975A0/xx
Publication of WO2015008066A1 publication Critical patent/WO2015008066A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • C08L5/16—Cyclodextrin; Derivatives thereof

Definitions

  • the invention relates to cyclodextrins and derivatised cyclodextrins, such as
  • sulphoalkyl ether ⁇ -cyclodextrin and in particular to a novel method for the synthesis thereof.
  • the invention is particularly concerned with producing sulphobutyl ether ⁇ - cyclodextrin.
  • the invention extends to novel compositions comprising sulphoalkyl ether ⁇ -cyclodextrins, and to the uses of such compositions, for example as excipients in order to improve the solubility and chemical stability of drugs in solution.
  • Sulphobutyl ether ⁇ -cyclodextrin is one of a class of polyanionic, hydrophilic water soluble cyclodextrin derivatives.
  • the parent ⁇ -cyclodextrin can form an inclusion complex with certain active pharmaceutical ingredients (API) with two benefits, the apparent aqueous solubility of the API increases and, if labile functional groups are included, chemical stability is improved.
  • API active pharmaceutical ingredients
  • the parent ⁇ -cyclodextrin suffers from two problems, including lower aqueous solubility and nephrotoxicity when given via injection, e.g. the intravenous route.
  • Figure l illustrates the chemical reaction for the synthesis of SBE ⁇ -CD from the reagents ⁇ -cyclodextrin ( ⁇ -CD) and 1, 4-butane sultone (BS).
  • US 6,153,746 (Shah et al, 2000) describes a batch synthesis of SBE ⁇ -CD, the process being effectively divided into three main stages, i.e. initial reagent dissolution, a sulphoalkylation reaction and final reaction quenching. The reaction is then followed by downstream processing and purification, and ultimate isolation of the solid SBE ⁇ -CD material.
  • a problem associated with using a batch synthetic method is that a high proportion of lower substituted SBE ⁇ -CD is observed. There is therefore a need to provide an improved synthetic method for producing substituted cyclodextrins, such as SBE ⁇ -CD.
  • SBE ⁇ -CD is currently used as an effective pharmaceutical excipient, and has been given the trade name Captisol (RTM).
  • RTM Captisol
  • SBE- ⁇ - CD-enabled drug products there are five US FDA-approved, SBE- ⁇ - CD-enabled drug products on the market: Nexterone (Baxter International); Geodon (Pfizer); Cerenia (Zoetis); Kyprolis (Onyx); Abilify (Bristol Myers Squibb).
  • Nexterone Boxter International
  • Geodon Pfizer
  • Cerenia Zoetis
  • Kyprolis Onyx
  • Abilify Bristol Myers Squibb
  • US 6,632,80361 Harmonic acid
  • Pfizer has developed the clinically important antifungal drug, voriconazole, formulated with SBE- -CD, as excipient.
  • a method for preparing sulphoalkyl ether ⁇ -cyclodextrin comprising contacting cyclodextrin with a base to form activated cyclodextrin, and separately contacting the activated cyclodextrin with an alkyl sultone to form sulphoalkyl ether ⁇ -cyclodextrin, characterised in that the sulphoalkylation reaction is carried out under continuous flow conditions.
  • sulphoalkyl ether ⁇ -cyclodextrin obtained or obtainable by the method according to the first aspect.
  • the inventors have found that the continuous flow nature of the sulphoalkylation reaction in the method of the first aspect results in a surprisingly superior process compared to the prior art batch process, because it exhibits a greater reaction efficiency and results in a much tighter control of substitution of the resultant sulphoalkyl ether ⁇ -cyclodextrin, which is preferably sulphobutyl ether ⁇ -cyclodextrin (i.e. SBE ⁇ -CD).
  • the continuous flow synthesis process of the invention substantially less than 50% of the amount of base (which is preferably sodium hydroxide) that is used in the prior art batch process, and only a 7:1 molar ratio of the alkyl sultone (which is preferably, 1, 4-butane sultone) to cyclodextrin instead of the 10:1 used by the prior art method.
  • base which is preferably sodium hydroxide
  • the alkyl sultone which is preferably, 1, 4-butane sultone
  • the sulphoalkylation reaction is carried out under continuous flow conditions, whereas the activation reaction may be carried out either continuously, batch, or fed-batch.
  • the activation reaction is carried out as a batch process while the sulphoalkylation reaction is carried out under continuous flow conditions.
  • the method of the invention in which the activation stage is batch and the sulphoalkylation reaction stage is continuous, results in lower concentrations of by-products, SBE- -CD with a higher average degree of substitution, and also most if not all of the alkyl sultone is reacted.
  • the cyclodextrin is ⁇ -, ⁇ - or ⁇ -cyclodextrin.
  • a- and ⁇ -cyclodextrin can be used as pharmaceutical excipients for instance in commercially available drugs such as Prostavasin, Opalamon ( ⁇ -CD) and Voltaren (modified ⁇ -CD).
  • the cyclodextrin is ⁇ -cyclodextrin.
  • the alkyl sultone may comprise propane sultone.
  • sulphoalkyl ether ⁇ - cyclodextrin preferably comprises sulphopropyl ether ⁇ -cyclodextrin ( ⁇ - ⁇ - ⁇ ).
  • the alkyl sultone comprises 1, 4-butane sultone.
  • the sulphoalkyl ether ⁇ -cyclodextrin comprises sulphobutyl ether ⁇ - cyclodextrin (SBE ⁇ -CD).
  • SBE ⁇ -CD sulphobutyl ether ⁇ - cyclodextrin
  • the batch method of preparing substituted sulphoalkyl ether ⁇ - cyclodextrin produces a higher concentration of lower degrees of sulphoalkyl ether ⁇ - cyclodextrin substitution than that produced using continuous flow.
  • the continuous flow process of the invention results in a lower concentration of lower substituted sulphoalkyl ether ⁇ -cyclodextrin (i.e. a degree of substitution value of 1-4) and surprisingly much higher concentrations of the higher substituted sulphoalkyl ether ⁇ - cyclodextrin (i.e. individual degrees of substitution values of 4-13).
  • the average degree of substitution (ADS) of the sulphoalkyl ether ⁇ - cyclodextrin produced by the method of the first aspect or the SBE ⁇ -CD of the second aspect is greater than 7, more preferably 7.3 or more, more preferably 8 or more, even more preferably 9 or more, and most preferably 10 or more.
  • the skilled person will appreciate that it is possible to calculate the substitution degree (i.e. the substitution envelope) by using the following Formula:
  • ADS ⁇ ((PAC) x (MT)/SCA x ioo)/ioo
  • PAC refers to the peak area count
  • MT refers to the migration time
  • SCA refers to the summation of corrected area.
  • composition comprising sulphobutyl ether ⁇ - cyclodextrin (SBE ⁇ -CD), wherein the average degree of substitution (ADS) is 7 or more, preferably 7.3 or more, preferably 8 or more, even more preferably 9 or more, and most preferably 10 or more.
  • ADS average degree of substitution
  • the continuous flow method of the invention provides a significant advantage.
  • the composition of the third aspect comprises SBE- -CD having a
  • composition of the third aspect comprises SBE- -CD having an SMF greater than 0.60, and more preferably greater than 0.61.
  • SMF Substitution Molecular Mass Fraction
  • the base may be an alkali metal hydroxide, for example sodium hydroxide, lithium hydroxide or potassium hydroxide. It is preferred that the base comprises sodium hydroxide.
  • the molar ratio of base (which is preferably sodium hydroxide) to cyclodextrin is preferably within the range of 2:1 to 22:1, preferably 6:1 to 20:1, more preferably 6:1 to 15:1, and even more preferably 6:1 to 14:1.
  • the preferred molar ratio of base to cyclodextrin is 6:1 to 14:1.
  • the most preferred molar ratio of base to cyclodextrin is 6:1 to 15:1.
  • the base employed to chemically activate the ⁇ -cyclodextrin hydroxyl groups, has a tendency to attack the alkyl sultone reagent, thereby reducing its effective concentration, and, as a result, reduces the average degree of substitution in the final product with the generation of low degree of substitution species.
  • the base is kept separate from the alkyl sultone, preferably 1, 4-butane sultone.
  • the base is first separately reacted with the cyclodextrin in order to produce the activated cyclodextrin. This reaction is preferably conducted in a first reservoir vessel.
  • the activation reaction may therefore be carried out as a batch or fed-batch process.
  • the base and cyclodextrin form an aqueous solution.
  • the activation reaction is preferably conducted at a temperature of about 50 to 95 °C, more preferably 60 to 70°C.
  • the activation reaction is preferably conducted at atmospheric pressure.
  • the alkyl sultone is contained within a second reservoir vessel.
  • the first and second vessels are not directly connected to each other, such that the sultone and the base do not react with each other.
  • the activated cyclodextrin (i.e. aqueous solution) and the alkyl sultone (i.e. pure) are preferably fed to a confluent 3-way junction where they are allowed to react to produce the substituted sulphoalkyl ether ⁇ -cyclodextrin.
  • the activated aqueous cyclodextrin and the alkyl sultone are preferably pumped at a controlled rate to the junction.
  • the molar ratio of sultone (preferably 1, 4-butane sultone) to cyclodextrin (preferably ⁇ -cyclodextrin) is preferably between about 7:1 and 33:1.
  • the molar ratio of sultone to cyclodextrin is 7:1 to 17:1.
  • the sulphoalkylation reaction is preferably conducted at a temperature of 60 to ioo°C, more preferably 65 to 95 °C, and even more preferably 60 to 70°C.
  • sulphoalkylation reaction is preferably conducted at atmospheric pressure.
  • the alkylation reaction may be carried out in a continuous stirred tank reactor (CSTR) or a flow reactor with efficient mixing and of suitable length to allow the reaction to complete within the reactor tubing.
  • CSTR continuous stirred tank reactor
  • the activation of ⁇ -cyclodextrin is an important process parameter prior to reaction and this must continue irrespective of the reactor architecture.
  • the method of the invention comprises contacting the cyclodextrin in a batch or fed-batch reaction with the base to form activated
  • cyclodextrin and separately contacting the activated cyclodextrin with an alkyl sultone to form sulphoalkyl ether ⁇ -cyclodextrin, wherein the sulphoalkylation reaction is carried out under continuous flow conditions.
  • the method comprises separately reacting ⁇ -cyclodextrin with sodium hydroxide in a batch or fed-batch reaction to form activated ⁇ -cyclodextrin, and then separately contacting the activated ⁇ -cyclodextrin with 1, 4- butane sultone to form SBE ⁇ -CD under continuous flow conditions.
  • the method comprises controlling the average degree of substitution (ADS) of sulphoalkyl ether ⁇ -cyclodextrin in the sulphoalkylation reaction by varying the base concentration in the initial activation reaction.
  • ADS average degree of substitution
  • the use comprises carrying out an initial activation reaction between cyclodextrin and the base to form activated cyclodextrin.
  • concentration of sodium hydroxide can be varied in the initial activation reaction in order to control and manipulate the average degree of substitution (ADS) of resultant sulphoalkyl ether ⁇ -cyclodextrin.
  • the unsubstituted parent ⁇ -CD is shown to induce irreversible nephrotic damage to the kidney cells when used as an excipient in injection formulations.
  • SBE ⁇ -CD causes reversible vacuolation of renal cells but not nephrotic damage and is therefore preferred for use in injectable formulations.
  • the method of the invention results in a lower concentration of low degree of substitution SBE ⁇ -CD species it is believed that the SBE ⁇ -CD may cause lower levels of physiological changes to renal cells. Accordingly, they believe that the SBE ⁇ -CD of the second aspect or the composition of the third aspect can be used to reduce changes in renal cells when used as a drug delivery system.
  • sulphoalkyl ether ⁇ -cyclodextrin of the second aspect or the composition of the third aspect, as a drug delivery system.
  • the drug delivery system is an excipient, which preferably exhibits little or no side effects with regard to renal physiology.
  • the sulphoalkyl ether ⁇ - cyclodextrin comprises sulphobutyl ether ⁇ -cyclodextrin ( ⁇ - ⁇ - ⁇ ).
  • a pharmaceutical excipient comprising the sulphoalkyl ether ⁇ -cyclodextrin of the second aspect, or the composition of the third aspect.
  • the sulphoalkyl ether- ⁇ -cyclodextrin comprises sulphobutyl ether ⁇ -cyclodextrin (SBE ⁇ -CD).
  • use of the continuous flow method of invention means that it is now possible to combine the two processes shown in Figure 22 (i.e. excipient production, and pharmaceutical production), to result in the 6-step process chain shown in Figure 23.
  • a method of preparing a pharmaceutical composition comprising preparing the pharmaceutical excipient according to the fifth aspect, and contacting the excipient with an active pharmaceutical ingredient (API) to produce a pharmaceutical composition.
  • API active pharmaceutical ingredient
  • the method of the invention means that three of the steps shown in Figure 22 can be omitted. Therefore, it is now unnecessary to transport the sulphobutyl ether cyclodextrin from the fine chemical manufacturer to the customer. This would also include warehousing, etc. Secondly, the sulphoalkyl ether ⁇ -cyclodextrin can be manufactured on a just-in-time, just-enough basis. Thirdly, one of the two expensive and time-consuming freeze or spray drying process steps can be avoided.
  • the method comprises contacting the excipient with an active
  • API pharmaceutical ingredient
  • the pharmaceutical excipient comprises sulphobutyl ether ⁇ -cyclodextrin.
  • the active pharmaceutical ingredient comprises voriconazole, ziprasidone, aripiprazole, maropitant, amiodarone, or carfilzomib, or their salts, solvates, polymorphs, pseudopolymorphs or co-crystals.
  • the method of the invention comprises separately reacting ⁇ - cyclodextrin with sodium hydroxide to form activated ⁇ - cyclodextrin, and then separately contacting the activated ⁇ -cyclodextrin with 1, 4- butane sultone to form SBE- -CD, all under continuous flow conditions.
  • the stoichiometry of the reaction can be readily controlled by varying the flow rates of the activated cyclodextrin solution and/ or liquid sultone.
  • a method for preparing sulphoalkyl ether ⁇ -cyclodextrin comprising contacting cyclodextrin with a base to form activated cyclodextrin, and separately contacting the activated
  • Figure 1 shows the chemical reaction for the synthesis of sulphobutyl ether ⁇ - cyclodextrin (SBE ⁇ -CD) from ⁇ -cyclodextrin (CD) and 1, 4-butane sultone (BS);
  • Figure 2 is a schematic representation for an embodiment of an apparatus for carrying out continuous flow (CF) synthesis for SBE ⁇ -CD according to the invention
  • Figure 3 shows the actual lab-based apparatus for carrying out a continuous flow synthesis for SBE ⁇ -CD
  • Figure 4 is a graph showing the changing amount of NaOH at 7:1 and 10:1 BS/CD mole ratio; 100% nominal sodium hydroxide is equivalent to the base content used in US 5,376,645 (Stella et 0/ 994)
  • Figure 5 shows electropherograms of batch manufactured SBE ⁇ -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE ⁇ -CD manufactured by a continuous flow process according to the invention, with a 8:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 6 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 11:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 7 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 14:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 8 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 17:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 9 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 19:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 10 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 23:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 11 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 28:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 12 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 33:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 13 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 7:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 6:1.
  • Figure 14 shows electropherograms of batch manufactured SBE- -CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE- -CD manufactured by a continuous flow process according to the invention, with a 7:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 9:1.
  • Figure 15 shows electropherograms of batch manufactured SBE-P-CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE-P-CD manufactured by a continuous flow process according to the invention, with a 7:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 11:1.
  • Figure 16 shows electropherograms of batch manufactured SBE-P-CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE-P-CD manufactured by a continuous flow process according to the invention, with a 7:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 14:1.
  • Figure 17 shows electropherograms of batch manufactured SBE-P-CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE-P-CD manufactured by a continuous flow process according to the invention, with a 10:1 butane sultone to P-cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to P-CD molar ratio is 6:1.
  • Figure 18 shows electropherograms of batch manufactured SBE-P-CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE-P-CD manufactured by a continuous flow process according to the invention, with a 10:1 butane sultone to P-cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to P-CD molar ratio is 9:1.
  • Figure 19 shows electropherograms of batch manufactured SBE-P-CD (US 6,153,746- Shah et al, 2000) as the solid line and SBE-P-CD manufactured by a continuous flow process according to the invention, with a 10:1 butane sultone to P-cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to P-CD molar ratio is 11:1.
  • Figure 20 shows electropherograms of batch manufactured SBE-P-CD (US 6,153,746- Shah, et al 2000) as the solid line and SBE-P-CD manufactured by a continuous flow process according to the invention, with a 10:1 butane sultone to P-cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to P-CD molar ratio is 14:1.
  • Figure 21 shows a Vapourtec integrated flow reactor and associated equipment that will ultimately be preferred for the integrated manufacture of the SBE-P-CD and API in a secondary pharmaceutical production manufacturing area to produce the drug product.
  • Figure 22 is a schematic representation of a conventional process chain for voriconazole Injection Based on the standard SBECD batch process and Fine Chemical Model (excipient production in white; secondary pharmaceutical production in grey).
  • Figure 23 is a schematic representation of a revised process chain for voriconazole Injection Based on an SBECD continuous flow (CF) process and Integrated Manufacture Model (excipient production in white; secondary pharmaceutical production in grey).
  • CF continuous flow
  • Figure 24 is a chromatogram of sulphobutylether ⁇ -cyclodextrin produced by the method described in US 6,153,746 (Shah, 2000), and tested according to the methods described in United States Pharmacopoeia 35/National Formulary 30
  • HPLC conditions are based on a gradient separation with a CD- Screen-DAP column and ELSD detection.
  • Figure 25 is a chromatogram of sulphobutylether ⁇ -cyclodextrin produced by the method according to the invention. Reaction conditions correspond to those used to generate Figure 20, and HPLC conditions are based on a gradient separation with a CD-Screen-DAP column and ELSD detection.
  • Figure 26 is a table showing shows a summary of the data adding the Average
  • Figure 27 is a table describing an attempt to produce material compliant with the USP35/NF30 monograph with the use of more moderate reaction conditions.
  • Figure 28 is a graph showing substitution molecular mass ratio for SBE- -CD.
  • Figure 29 is a graph showing the molecular weight and individual degree of substitution for SBE ⁇ -CD.
  • the inventors have developed a novel continuous flow (CF) method for the synthesis of sulphoalkyl ether- ⁇ -cyclodextrin, for example sulphobutyl ether ⁇ -cyclodextrin (SBE- ⁇ - CD).
  • CF continuous flow
  • the invention includes novel compositions comprising sulphoalkyl ether ⁇ - cyclodextrins, and to therapeutic uses of such compositions, for example to improve the solubility and chemical stability of drugs in solution.
  • Beta cyclodextrin ( ⁇ -CD), 1, 4-Butane Sultone (BS), Water for injections and sodium hydroxide (NaOH).
  • CSTR Continuous stirred tank reactor
  • the set-up for the continuous flow experiments consisted of two Masterflex pumps (8, 10) connected to a double 10ml (i.e. two 10ml chambers) jacketed continuous stirred tank reactor (CSTR) or holding chamber (14) used as a holding chamber/sight glass.
  • the two pumps (8, 10) were connected to the CSTR/holding chamber (14) via a three- way connector (12) and PTFE tubing.
  • Non-return valves were fitted in line in the vicinity of the three-way connector (12) to prevent the reagent stream reverse flow as a result of differential flow pressure in either of the feed lines.
  • the PTFE tubing was put in a water bath to maintain temperature at approximately 50- 6o°C. In another embodiment, the PTFE tubing was put in a water bath to maintain temperature at approximately 6o-ioo°C.
  • a stock solution of ⁇ -CD in NaOH solution (4) was first prepared as follows: I5g of ⁇ -CD (1.32 x io ⁇ 2 mole) was added with stirring to an aqueous solution composed of 6g of NaOH in 30ml water. This solution was maintained between 6o-70°C with a hotplate stirrer.
  • pump (8) was used to deliver stock ⁇ -CD solution into the CSTR (14) via a three way connector (12) where the reaction initially takes place, while pump (10) was used to also deliver neat butane sultone (6), at ambient temperature, through the connector (12) into the CSTR (14).
  • the neat sultone (6) can be heated to 60-90 °C.
  • the CSTR (14) contained two 10ml chambers and was provided to increase the residence time for the reaction to continue, having started in the connector (12).
  • pump (8) was first turned on to feed the ⁇ -CD until it reached the first chamber of the CSTR (14), after which pump (10) was then turned on to feed the butane sultone into the CSTR (14).
  • pumps (8, 10) are both activated at the same time in order to avoid pumping pure ⁇ -CD through the system to produce higher than desirable unreacted precursor that would ultimately need to be removed by downstream processing.
  • An internal vortex circulation was generated within the continuous flowing reaction stream within the CSTR (14), which ensured rapid mixing. Efficient stirring appears to be very important to the success of the process.
  • the reaction solution was delivered via pumps (8, 10) into the CSTR (14) in a continuous manner.
  • the PTFE tubing is about 30cm in length and is not sufficient for the reaction to complete prior to entry into the CSTR (14). As two phases are seen in the first chamber of the CSTR (14), it is most likely that small volumes of the heated reagents are delivered and react there.
  • the second chamber of the CSTR (14) and the receiving vessel both contain clear liquid suggesting that the reaction is complete upon exit from the first chamber of the CSTR (14).
  • High flow rates will deliver unreacted material to the second chamber and, in extreme circumstances, to the receiving vessel.
  • the crude product was harvested in a 20ml sample bottle.
  • Table 1 The relationship between pump drive speed and flow rate giving rise to different butane sultone- ⁇ -cyclodextrin molar ratios - constant ⁇ -cyclodextrin flow rate.
  • FIG. 2 and 3 there are shown embodiments of the apparatus 2 for the continuous flow synthesis of SBE-P-CD.
  • Two reservoirs (4), (6) are primed, the first reservoir (4) containing "activated" ⁇ -cyclodextrin and sodium hydroxide in an aqueous solution, and the second reservoir (6) containing pure 1,4-butane sultone.
  • a first peristaltic pump (8) was turned on to feed the ⁇ -cyclodextrin and sodium hydroxide in aqueous solution through a three-wayjunction (12) with non-return valves.
  • a second peristaltic pump (10) was turned on to feed the 1, 4-butane sultone also through the junction (12) where it reacted with the ⁇ -cyclodextrin.
  • the stoichiometry of the reaction could be controlled by mixing the two reaction streams at differential rates, and the ratio of ⁇ -cyclodextrin to sodium hydroxide could be adjusted in the reservoir (4) prior to mixing with 1, 4-butane sultone.
  • the amount of SBE ⁇ -CD produced in the process is therefore a function of pumping time, and not equipment scale.
  • the residence time of the reaction between the ⁇ -cyclodextrin/NaOH solution and 1, 4- butane sultone was increased by passing the mixture from the outlet of the three-way junction (12) to a holding chamber/ sight glass or continuous stirred tank reactor (CSTR) (14) where further reaction took place.
  • the CSTR (14) could be replaced in whole or in part with a temperature controlled coiled tubing of sufficient length. This would provide appropriate level of turbulence and residence time for the coupling reaction to complete efficiently.
  • the inventors' primary focus was to study the complexity of the sulphoalkylation reaction in the flow synthesis mode. It was therefore necessary to dialyse (18) the reaction effluent (16), freeze dry it (20) and then analyse it (22). Under commercial conditions, the SBE ⁇ -CD effluent (16) leaving the CSTR (14) would be connected to the downstream processing elements, e.g. continuous dialysis, flow-through
  • FIG. 5-20 there are shown electropherograms for the standard batch (standard) and continuous flow (CF) synthesis of SBE- -CD at the different BS: ⁇ -CD molar ratios resulting from differential pump speeds at a constant ⁇ -CD: sodium hydroxide mass ratio, or at different ⁇ -CD: sodium hydroxide mass ratios for two different BS: ⁇ -CD molar ratios as indicated.
  • the standard curve (solid line) corresponds to the known batch manufacture method of SBE ⁇ -CD, as described in US 6,153,746 (Shah et al, 2000).
  • the dotted trace in each graph however is for an SBE- ⁇ - CD sample produced by a continuous flow (CF) synthesis process according to the invention.
  • FIG. 6 there is shown the electropherograms for standard sample of Batch produced SBE ⁇ -CD and SBE ⁇ -CD produced by continuous flow synthesis at a 4:8 BS/CD drive speed and therefore a given BS: CD mole ratio as shown in Table 1.
  • Table 1 there are 10 peaks for the CF method and only 9 peaks for the Batch method. The number of peaks is indicative of the degree of substitution for the derivatives.
  • Figure 7 there is shown the electropherograms for standard sample of Batch produced SBE-P-CD and SBE-P-CD produced by continuous flow synthesis at a 5:8 BS/CD drive speed, at a given BS: CD mole ratio as shown in Table 1.
  • the two electropherograms show coincidence which indicates equivalence of substitution envelope. Both plots show about 9 distinguishable peaks which correspond to the degree of substitution.
  • FIG. 9 there is shown the electropherograms for standard sample of Batch produced SBE-P-CD and SBE-P-CD produced by continuous flow synthesis at a 7:8 BS/CD drive speed and at given BS: CD mole ratio as shown in Table 1.
  • the electropherogram for the continuous flow shows an intense peak between 4 and 5 minutes, this peak possibly indicating the presence of a reaction impurity.
  • the BS: P- CD mole ratio indicates an excess of BS.
  • FIG. 11 there is shown the electropherograms for standard sample of Batch produced SBE-P-CD and SBE-P-CD produced by continuous flow synthesis at a 10:8 BS/CD drive speed at given BS: CD mole ratio as shown in Table 1.
  • the electropherogram for the continuous flow shows an intense peak between 4 and 5 minutes, again this peak possibly indicating the presence of a reaction impurity.
  • the BS: P-CD mole ratio indicates an excess of BS.
  • FIG 12 there is shown the electropherograms for standard sample of Batch produced SBE-P-CD and SBE-P-CD produced by continuous flow synthesis at a 12:8 BS/CD drive speed at given BS: CD mole ratio as shown in Table 1.
  • the electropherogram for the continuous flow also shows an intense peak between 4 and 5 minutes, this peak possibly indicating the presence of a reaction impurity.
  • the BS: ⁇ - CD mole ratio indicates an excess of BS.
  • FIG. 13 there is shown the electropherograms batch manufactured SBE- P-CD as the solid line and SBE-P-CD manufactured by the continuous flow process with a 7:1 butane sultone to ⁇ -cyclodextrin molar ratio as the dotted line.
  • the sodium hydroxide to ⁇ -CD molar ratio is 6:1.
  • electropherograms indicates an equivalent 'Substitution Envelope', i.e. degree of substitution distribution.
  • the continuous flow synthesis process of the invention requires less than 50% of the sodium hydroxide that is used in the prior art batch process (Stella et al, 1994), and a 7:1 molar ratio of 1, 4-butane sultone to ⁇ -cyclodextrin instead of the 10:1 used by the prior art method. This finding was completely unexpected, given that the inventors' expectation was at best an equivalent synthetic efficiency.
  • ADS average degree of substitution
  • FIG. 14 there is shown the electropherograms for standard sample of Batch produced SBE- -CD and SBE- -CD sample produced by continuous flow synthesis.
  • the continuous flow uses only 75% sodium hydroxide compared to the amount used in the batch process (Stella et al, 1994), and a 7:1 molar ratio of 1, 4-butane sultone to ⁇ -cyclodextrin instead of the 10:1 used by the prior art method.
  • the electropherogram for the continuous flow shows a positive shift of the substitution envelope and change in the modal degree of substitution from ⁇ 6min to 8 min, and this indicates a higher average degree of substitution can be achieved more economically.
  • FIG. 16 there is shown there is shown the electropherograms for standard sample of Batch produced SBE- -CD and SBE- -CD sample produced by continuous flow synthesis.
  • the continuous flow uses 25% more sodium hydroxide compared to the amount used in the batch process (Stella et al, 1994), and a 7:1 molar ratio of 1, 4-butane sultone to ⁇ -cyclodextrin instead of the 10:1 used by the prior art method .
  • the electropherogram for the continuous flow shows a positive shift of the substitution envelope and further change in the modal degree of substitution from ⁇ 6min to 8 min, very small population of lower degrees of substitution
  • FIG. 17 there is shown the electropherograms for standard sample of Batch produced SBE- -CD and SBE- -CD sample produced by continuous flow synthesis.
  • the continuous flow uses only 50% sodium hydroxide compared to the amount used in the batch process (Stella et al, 1994), and an increase from 7:1 to 10:1 molar ratio of 1, 4-butane sultone to ⁇ -cyclodextrin.
  • the electropherogram for the continuous flow shows an intense peak at 5 minutes this possibly indicates the presence of a reaction impurity.
  • FIG. 18 there is shown the electropherograms for standard sample of Batch produced SBE- -CD and SBE- -CD sample produced by continuous flow synthesis.
  • the continuous flow uses only 75% sodium hydroxide compared to the amount used in the batch process (Stella et al, 1994), and an increase from 7:1 to 10:1 molar ratio of 1, 4-butane sultone to ⁇ -cyclodextrin.
  • the electropherogram for the continuous flow shows a positive shift of the substitution envelope and change in the modal degree of substitution from ⁇ 6min to 8 min, this indicates a higher average degree of substitution.
  • FIG. 19 there is shown there is shown the electropherograms for standard sample of Batch produced SBE- -CD and SBE- -CD sample produced by continuous flow synthesis.
  • the continuous flow uses the same amount of sodium hydroxide compared to the amount used in the batch process (Stella et al, 1994), and a 10:1 molar ratio of 1, 4-butane sultone to ⁇ -cyclodextrin, identical conditions used by (Stella et al, 1994).
  • the electropherogram for the continuous flow shows a positive shift of the substitution envelope and a change in the modal degree of substitution from ⁇ 6 min to 8 min, a smaller population of lower degrees of substitution (migration time range 2-7 minutes) and this indicates a higher degree of substitution.
  • FIG 20 there is shown an electropherogram of batch-produced (Shah et al, 2000) and continuous flow-produced standard SBE- -CD.
  • the continuous process used to produce the material shown in Figure 20 used 25% more sodium hydroxide than the batch process (Stella et al, 1994), with an increase in the molar ratio of 1,4- butane sultone to ⁇ -cyclodextrin from 7:1 to 10:1.
  • the material produced by flow synthesis is novel and demonstrates a positive skew in the Substitution Envelope with a smaller population of lower degrees of substitution (migration time range 2-7 minutes) and the modal degree of substitution changing from ⁇ 6 minutes to ⁇ 8 minutes. It is concluded therefore that the continuous flow method of the invention results in an increase in efficiency (more efficient activation of ⁇ -cyclodextrin hydroxyl groups by sodium hydroxide; less consumption of 1, 4-butane sultone) resulting in a higher degree of substitution.
  • SB ⁇ -CD in an injectable pharmaceutical drug product (i.e. voriconazole) is described in the 2003 Pfizer patent, US 6,632,80361.
  • the formulation of an injectable form of voriconazole is described in Table 4.
  • Table 4 Formulation of an injectable form of voriconazole using the 8 ⁇ - ⁇ - ⁇ platform
  • the manufacturing process is as follows: 1. Add SBE- -CD to 80% of the final volume of Water for Injections with constant stirring until dissolved;
  • SBECD could be manufactured on a just-in-time, just-enough basis.
  • the frequency of low degree of substituted SBECD species using the prior art batch reaction is much higher than with using the continuous flow chemistry of the invention.
  • the continuous flow method of the invention enables a greater reaction efficiency.
  • the novel species produced by the continuous flow process have a higher degree of substitution with a tighter distribution of substitution, as well as a higher average degree of substitution per se.
  • the reaction proceeds in a continuous manner, i.e. once the pumps (8, 10) have started they are not switched off until completion of the reaction. It is now generally considered that the main reaction takes place in the first CSTR chamber (14). The reaction takes place at a low temperature (65-ioo°C) and atmospheric pressure.
  • the CSTR-process handles the ⁇ -cyclodextrin-sodium hydroxide solutions and butane sultone as an immiscible, two phase system.
  • the activation process must be conducted at elevated temperature (65-ioo°C) and for a specified time after the ⁇ -cyclodextrin has dissolved in the aqueous sodium hydroxide solution.
  • the activation process has typically taken 30 minutes at this scale; the major indicator of completion is the colour change which could be measured colourimetrically.
  • sulphobutylether ⁇ -cyclodextrin to improve the selectivity of the analytical method.
  • High performance liquid chromatography with evaporative light scattering detection (ELSD) is used for the separation of sulphobutylether ⁇ -cyclodextrin into its substituted constituents in order to determine the average degree of substitution.
  • Identification of each substituted cyclodextrin is determined by comparing the retention times of the standard, produced by the method described in US 6,153,746 (Shah, 2000), and tested according to the methods described in USP35/NF30 with that of a material produced using the processing method described herein.
  • FIG. 24 A typical chromatogram for the standard material produced using a prior art batch method described in US 6,153,746 (Shah, 2000) is shown in Figure 24. Upon further examination of Figure 24, it can be seen that material produced by the prior art process has a range of substitution from Degree of Substitution 2 to 10. The Average Degree of Substitution is 6.6.
  • the chromatogram for the sulphobutylether ⁇ -cyclodextrin produced using the method of the invention and corresponding to Figure 20 is shown in Figure 25. It is readily seen that a stable baseline is generated facilitating integration and subsequent processing of the signal.
  • Figure 25 indicates that material produced using the invention has a range of substitution from Degree of Substitution 3 to 13. The Average Degree of Substitution is 10.4, as described below.
  • the method of the invention does not produce any detectable di-substituted sulphobutylether ⁇ -cyclodextrin and produces significant quantities of Degree of Substitution 11-13 not detected in the US 6,153,746 (Shah, 2000) material.
  • the inventors also have the corresponding HPLC traces corresponding to the electropherograms in Figures 12 to 20. The power of the technique gives access to descriptive statistics.
  • the Individual Degree of Substitution (IDS n ) is calculated using the following formula:
  • PA L Peak area corresponding to lowest degree of substitution seen on the chromatogram
  • PA H Peak area corresponding to highest degree of substitution seen on the chromatogram
  • ADS ⁇ (IDS n x n)/ 100
  • Table 1 shows data for the chromatogram shown in Figure 25. This can now be processed using Equations 1-3 as follows: Table 1: Integration table of the chromatogram of sulphobutylether ⁇ -cyclodextrin produced by the method of the invention. Reaction conditions correspond to those used to generate Figure 20 HPLC conditions are based on a gradient separation with a CD-Screen-DAP column and ELSD detection
  • ⁇ PA ⁇ PA L + PA L+1 ... PA H
  • ⁇ PA 0.271 + O.507 + 1.455 + 3-142 + 5-221 + 13.283 + 24.842 + 46.056 + 53.920 + 39.220 + 16.570
  • x 100 2.553219
  • x 100 6.495767
  • the material described in Figure 25 therefore has an average degree of substitution of 10.4, which is substantially higher than material produced by batch manufacture or fully continuous flow process.
  • the table shown in Figure 26 shows a summary of the data adding the Average Degree of Substitution data and dispersion data.
  • the number of pendant sulphobutyl groups on the cyclodextrin determines the Individual Degree of Substitution metric and the Substitution Envelope.
  • the molecular mass of beta cyclodextrin is 1134.98 Dalton.
  • a proton is removed, and replaced with a linear butane sultone function with a molecular mass of 136.17 Dalton.
  • the resulting molecular mass of individual degree of substitution (IDS), where n i is 1270.15 Dalton. If one considers 5 the mass associated with the cyclodextrin ring as a fraction of the total mass, it is
  • the USP-NF Peak Area Percentage describes a series of Proven Acceptable Ranges for an upper and lower distribution of IDSn in which a 'Substitution Envelope' resides. With a shift in IDSn to higher values using the process of the invention, it is possible to shift the envelope. As shown in Figure 27, it is possible to 'de-tune' the process of the invention to broadly comply with the USP-NF Envelope, and this is not possible using the fully batch or fully continuous processes described in the prior art.
  • the sulphobutylether ⁇ - cyclodextrin composition produced by the CSTR process according to the invention described herein, is novel in two respects: (i) it has an unprecedented high average degree of substitution; and (ii) the existence of highly substituted species with IDS n higher than 10.
  • the CSTR process depends upon pre-activation of the ⁇ -cyclodextrin feedstock by sodium hydroxide where the extent of activation determines the Average Degree of Substitution. The process allows control of Average Degree of Substitution by varying the sodium hydroxide concentration.
  • the process can be used to produce material with a high Average Degree of Substitution. It will be possible to manufacture material compliant with the USP35/NF30 specification for sulphobutylether ⁇ - cyclodextrin. The process enables the production of sulphobutylether ⁇ -cyclodextrin on a 'just in time', 'just enough' basis in a small manufacturing footprint.

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Abstract

La présente invention concerne un procédé de préparation de sulfoalkyle éther- β-cyclodextrine. Le procédé consiste à mettre tout d'abord la cyclodextrine avec une base pour former de la cyclodextrine activée. Le procédé consiste ensuite à mettre en contact séparément la cyclodextrine activée avec un alkyle sultone pour former un sulfoalkyle éther- β-cyclodextrine. La réaction d'activation est effectuée par lots et la réaction de sulfoalkylation est menée dans des conditions de flux continu.
PCT/GB2014/052173 2013-07-17 2014-07-16 Cyclodextrine WO2015008066A1 (fr)

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CN112557541B (zh) * 2020-12-08 2022-07-12 河北科技大学 一种枸橼酸马罗匹坦及其有关物质的检测方法
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GB2519832A (en) 2015-05-06
EP3022231B1 (fr) 2018-04-18
JP2016525600A (ja) 2016-08-25
GB2586104A (en) 2021-02-03
GB2519832B (en) 2021-03-03
GB201312737D0 (en) 2013-08-28
US11117978B2 (en) 2021-09-14
HUE038911T2 (hu) 2018-12-28
CA2919501A1 (fr) 2015-01-22
PT3022231T (pt) 2018-06-11
US10239961B2 (en) 2019-03-26
EP3022231A1 (fr) 2016-05-25
AU2014291800A1 (en) 2016-02-11
US20160024229A1 (en) 2016-01-28
US20150025023A1 (en) 2015-01-22
GB202015609D0 (en) 2020-11-18
KR20160031019A (ko) 2016-03-21
CL2016000082A1 (es) 2016-09-23
AP2016008975A0 (en) 2016-01-31
MX2016000553A (es) 2016-08-01
GB2586104B (en) 2021-03-31

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